International Research Fellowship Program : Using Drosophila to Study the Biology of polyQ Neurodegeneration

0651049齐格霍恩国际研究奖学金计划使美国科学家和工程师能够在国外进行9至24个月的研究。该计划的奖项提供了联合研究的机会，并利用国外独特或互补的设施、专业知识和实验条件。该奖项将支持Suzanne L.Ziegenhorn博士与Gaiti Hasan博士在印度班加罗尔国家生物科学中心合作的为期24个月的研究奖学金。该项目由国际科学与工程办公室的非洲、近东和南亚计划(ANESA)提供支持。最近，GABA能中棘纹状体神经元(MSN)中钙调节的放松与这些细胞对多聚Q扩展亨廷顿蛋白(Htt EXP)的特异性敏感性有关，并可能解释为什么这些细胞是亨廷顿病(HD)的退变靶点。在小鼠的MSN中，已证明Httex而不是Htt使肌醇(1，4，5)-三磷酸受体1(InsP3R1)对InsP3敏感，导致钙释放增加。如果钙功能障碍确实促进了HD的进展，一系列新的治疗方法，即钙信号抑制剂，可能会用于治疗患有这种疾病的患者。果蝇是一个很好的生物，可以用来研究错乱的钙稳态对神经退行性疾病进展的潜在贡献，因为基因组中只有一个InsP3R基因(Itpr)。鉴于果蝇InsP3R的功能与小鼠受体的相似性，以及越来越多的证据表明HD是一种以钙稳态失调为特征的疾病，研究iTPR在调节由多聚Q扩展的人类Huntington诱导的果蝇光感受器神经元退化中的作用可能会揭示疾病的状态。对几个可行的异等位itpr突变组合的InsP3R通道功能进行了评估，结果导致将这些组合分为三类，即对InsP3反应释放更多钙的组合，释放较少的组合，以及似乎对野生型反应相似的组合。为了评估不同类型的InsP3R介导的钙离子功能障碍对神经退行性变的影响，将含有不同长度多Q束的Htt的N端多聚Q结构域片段的表达靶向于存活的异等位基因itpr突变体的光感受器神经元。光感受器退变的影响是在一段时间内确定的，以显示Htt EXP诱导的退变的进行性。此外，为了检验Htt exp引起的退化是否可以通过影响钙离子的药物处理来预防、逆转或增强，用抑制或促进Ca~(2+)信号转导的药物处理表达Htt exp的幼虫，并检测这些化合物对光感受器退化的影响。此外，通过利用其他已知钙通道和传感器中的现有突变，细胞内钙信号可以通过遗传手段改变，以确定它们对表达Htt exp的果蝇组织退化的影响。减轻HD症状严重程度或推迟HD症状发生的化合物该系统可能作为HD的一种潜在治疗方法，从而打开了许多其他通过调节钙信号而发挥作用的化合物可能用于治疗这种疾病的可能性。

0651049ZiegenhornThe International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-four-month research fellowship by Dr. Suzanne L. Ziegenhorn to work with Dr. Gaiti Hasan at the National Centre for Biological Sciences in Bangalore, India. Support for this project is provided by the Office of International Science and Engineering's Africa, Near East, and South Asia Program (ANESA).Calcium deregulation in GABAergic medium spiny striatal neurons (MSNs) has recently been implicated in the specific sensitivity of these cells to polyQ expanded Huntingtin (Htt exp) and may explain why these cells are targeted for degeneration in Huntington's Disease (HD). In mouse MSNs, it has been demonstrated that Httexp, but not Htt, sensitizes the inositol (1,4,5)-triphosphate receptor type 1 (InsP3R1) to InsP3, leading to increased Ca2+ release. If indeed calcium dysfunction contributes to HD progression, a family of new therapies, namely Ca2+ signaling inhibitors, may be of use in treating patients who suffer from this disorder.Drosophila is an excellent organism in which to examine the potential contribution of deranged Ca2+ homeostasis to neurodegenerative disease progression as there is a single InsP3R gene (itpr) in the genome. Due to the functional similarity of Drosophila InsP3R to the mouse receptor and the growing body of evidence that suggests that HD is a disorder characterized by Ca2+ homeostasis deregulation, investigating the role of itpr in regulating degeneration of Drosophila photoreceptor neurons induced by polyQ-expanded human Huntington may reveal insights into the disease state. The InsP3R channel function has been assessed for several viable heteroallelic itpr mutant combinations and the results have led to the grouping of these combinations into three classes, those that release more Ca2+ in response to InsP3, those that release less, and those that appear to respond similarly to wild-type. To assess the effect of various types of InsP3R-mediated Ca2+ dysfunction on neural degeneration, expression of the N-terminal polyQ domain-containing fragment of Htt with polyQ tracts of varying lengths is targeted to the photoreceptor neurons in the viable heteroallelic itpr mutants. The effects on photoreceptor degeneration are determined over a time course to show the progressive nature of Htt exp-induced degeneration. Further, to examine if the degeneration that results from Htt exp can be prevented, reversed, or enhanced by treatment with drugs that affect Ca2+, larvae that are expressing Htt exp are treated with drugs that either inhibit or promote Ca2+ signaling and the effect of these compounds on photoreceptor degeneration are assayed. Additionally, intracellular Ca2+ signals can be altered by genetic means by utilizing existing mutations in other known Ca2+ channels and sensors to determine their effects on tissue degeneration in flies expressing Htt exp. Compounds that reduce the severity or delay the onset of HD symptoms this system may serve as a potential therapy for HD, opening up the possibility that many additional compounds that act by modulating Ca2+ signaling may be of use in the treatment of this disorder.